Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/10—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/10—Spiro-condensed systems

Definitions

• the present invention relates to novel spiro-3-heteroazolidine compounds and salts thereof, a process for the preparation of the compounds as well as a pharmaceutical agent comprising at least one of the compounds to cure or prevent a complication due to diabetes.
• An object of the invention lies in providing a novel inhibition substance to aldose reductase enzymes to prevent an accumulation of sorbitol and galactitol in vivo and in turn to make prevention and curing of complications due to diabetes possible.
• a novel spiro-3-hetero-azolidine compound represented by the formula ##STR1## wherein T represents sulfur atom or hydrogen substituted nitrogen atom, U represents oxygen atom, sulfur atom or imino radical, one of V and W represents hydrogen atom, halogenomethyl radical, 1H-tetrazol-5-yl radical,--COOR, ##STR2## --CH 2 OR 3 or ##STR3## the other of V and W represents hydrogen atom or alkyl group, X represents oxygen atom or sulfur atom, Y and Z are same or different and each represents hydrogen atom, halogen atom, alkyl group, alkoxy group or alkylmercapto group, R is hydrogen atom, alkyl group, --(CH 2 CH 2 O)nCH 3 or substituted phenyl radical, R 1 and R 2 are same or different and each represents hydrogen atom, alkyl, --(CH 2 CH 2 O)nCH 3 or substituted phenyl radical, R 1 and R 2 are same or different and
• the compounds (I) have an effective inhibition action to aldose reductase enzymes and that the toxicity thereof is quite low.
• the alkyl group may be of straight-chain alkyl radicals, branched-chain alkyl radicals or cycloalkyl radicals.
• straight-chain alkyl radicals one having 1 to 6 carbon atoms, for instance methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and the like may be listed.
• branched-chain alkyl radicals isopropyl, isobutyl, s-butyl, t-butyl and the like may be listed.
• cycloalkyl radicals one having three or more carbon atoms, for instance cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like may be listed.
• halogenomethyl radical fluoromethyl, chloromethyl, bromomethyl, iodomethyl or the like may be listed.
• substituents for the substituted phenyl radical chlorine atom, bromine atom, methyl radical, methoxy radical and hydroxy radicals in o, m or p-position may be listed.
• substituents R 1 and R 2 represent together the heterocyclic ring with nitrogen or oxygen atom, pyrrolidino, morpholino, piperidino, piperidino and the like radicals may be listed.
• alkoxy and alkylmercapto radicals those having a straight-chain alky radical, for instance methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy or the like as well as methylmercapto, ethylmercapto, n-propylmercapto, n-butylmercapto, n-pentylmercapto, n-hexylmercapto or the like may be listed, and those having a branched-chain alkyl, for instance isopropoxy, isobutoxy, s-butoxy, t-butoxy or the like as well as isopropylmercapto, isobutylmercapto, s-butylmercapto, t-butylmercapto or the like may be listed.
• halogen atom fluorine, chlorine, bromine and iodine may listed but the fluorine is most prefer
• the salt of the compounds (I) means those acceptable for employing the same as an effective component in pharmaceutical agents and as concrete examples, those with cations such as sodium, potassium, calcium, magnesium and the like may be listed.
• Each of the compounds (I) according to the invention has two asymmetric carbon atoms in its structure and thus have two kinds of stereo isomers and optical isomers thereof. It should be noted that those are, of course, included in scope of the invention.
• a metallic cyanide and ammonium carbonate In this case, sodium cyanide, potassium cyanide and the like may be listed as the metallic cyanide.
• the reaction may be carried out in the presence of a solvent and at 50° to 150° C. for about 4 hours to 2 days.
• an aqueous reaction solution (when the solvent is water and if the solvent is not water, the reaction solution diluted with water) is acidified to cause a preciptitation of the objective compound, which means an isolation thereof can easily be carried out.
• any of the comopounds (II) as the starting material for the process according to the invention can be synthesized by an optional method.
• sulfuric acid, hydrochloric acid or the like mineral acid is acted to the carboxylic acid in methanol, ethanol, propanol or the like alkanol
• the carboxylic acid and an alcohol compound are condensed in benzene, toluene or the like non-polar solvent and with use of an aromatic sulfonic acid
• the carboxylic acid and an alcohol compound are condensed with dicyclohexylcarbodiimide or the like condensation agent to form the ester derivative
• the carboxylic acid and an amine are condensed in pyridine, dioxane or the like inert solvent and with use of tetrachlorosilane, dicyclohexylcarbodiimide or the like condensation agent to form the carboxamide derivative.
• the hydroxymethyl derivatives, halogenomethyl derivatives, alkoxymethyl derivatives and aminomethyl derivatives can also be prepared by strating from said carboxylic acid.
• the following is routes for synthesizing the derivatives. ##STR9## wherein R, R 1 , R 2 , X, Y and Z have the meanings as referred to, V' is hydrogen atom or alkyl group, and Alk means alkyl group.
• the compound among those shown by the formula I-B, wherein the substituent U is imino radical, namely the compound represented by the formula ##STR12## wherein V, W, X, Y and Z have the meanings as referred to can be prepared by reacting in the presence of a base the compound of formula III with thiourea.
• a base the compound of formula III
• sodium acetate or the like may be used as the base and acetic acid, cyclic ether (tetrahydrofuran, dioxane or the like), N,N-dialkylamide or the like may be used as a solvent.
• a reaction temperature for the process is between about 60° and about 150° C. but is preferable to carry out the reaction with use of the acetic acid as the solvent and at its reflux temperature.
• the compound among those shown by the formula I-B, wherein the substituent U is oxygen atom, namely the compound represented by the formula ##STR13## wherein V, W, X, Y and Z have the meanings as referred to can be prepared by hydrolizing the compound I-B-1. It is convenient that the hydrolysis is carried out under acidic condition, namely in the presence of a mineral acid and in an alkanol (methanol, ethanol or the like) and at reflux temperature of the solvent.
• This synthetic reaction is carried out at 60° to 150° C. with use of aceton, acetic acid, cyclic ether, N,N-dialkylamide or the like solvent but it is preferable to carry out with use of the acetic acid as solvent and at its reflux temperature.
• the compound III as starting material for this process can be prepared with use of a method known per se, for instance by halogenizing with use of thionylchloride, phosphorous tribromide or the like a compound represented by the formula ##STR15## wherein V, W, X, Y and Z have the meanings as referred to.
• the spiro-3-heteroazolidine compounds according to the invention shows a quite low toxicity of higher than 6000 mg/kg in oral dosage thereof and a high anti- or inhibition activity to aldose reductase enzymes.
• 6-fluoro-2,3-dihydro-2',5'-dioxo-spiro(4H-1-benzopyran-4,4'-imidazolidine)-2-carboxamide and 6-fluoro-2,3-dihydro-N,N-dimethyl-2',5'-dioxo-spiro(4H-1-benzopyran-4,4'-imidazolidine)-2-carboxamide are excellent in inhibition of polyol accumuration in sciatic nerve.
• aqueous basic solution was washed with 500 ml of ethyl acetate, acidified with 6N-hydrochloric acid and extracted with 1 liter of ethyl acetate.
• the organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give 76.9 g (89.3%) of the desired compound.
• a mixture consisting of potassium cyanide (37.1 g, 0.57 mol), ammonium carbonat (164 g, 1.7 mol) and 6-fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid (60.0 g, 0.29 mol) (obtained through the process as described in the Item d of said Reference Example 1) was heated at 65°-70° C. for 24 hours under stirring and then at reflux temperature for 15 minutes. The reaction mixture was cooled to room temperature and then acidified to pH 1 with concenrated hydrochloric acid. Resulting precipitate was subsequently filtered, washed with water and then recrystallized from water to give 48.8 g (60.1%) of the desired compound.
• the compound obtained through said process in this Example was a single diastereoisomer.
• Example 3 The procedure described in Example 3 was reported except that ethylamine hydrochloride was employed as the starting material in same molar amount (2.72 g, 0.024 mol) in place of monomethylamine hydrochloride. In this particular case, 4.80 g (78.1%) of the desired compound were obtained.
• Example 3 The procedure described in Example 3 was repeated except that dimethylamine hydrochloride was employed as the starting material in same molar amount (1.96 g, 0.024 mol) in place of monomethlamine hydrochloride. In this particular case, 4.60 g (75.4%) of the desired compound were obtained.
• Example 6 The procedure described in Example 6 was repeated except that n-butylamine was employed as the starting material in same molar amount (1.8 g, 0.024 mol) in place of n-propylamine. In this particular case, 4.40 g (65.7%) of the desired compound were obtained.
• Example 6 The procedure described in Example 6 was repeated except that 3,6,9,12-tetraoxatridecylamine was employed as the starting material in same molar amount (5.0 g, 0.024 mol) in place of n-propylamine. In this particular case, 7.20 g (77.1%) of the desired compound were obtained.
• reaction mixture was evaporated in vacuo to give a semi-solid residue which was partitioned between 50 ml of chloroform and 50 ml of water.
• the organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give a pale yellow oil which was chromatographed on silica gel, eluting with ethyl acetate to give 3.9 g (82.5%) of the desired refined compound as a colorless oil.
• the aqueous solution was acidified to pH 1 under cooling (10° to 15° C.) by addition of concentrated hydrochloric acid and extracted with 400 ml of ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give a solid which was recarystallized from methanol to give 8.7 g (82.0%) of the desired refined compound.
• a dry solid pharmaceutical composition was prepared by blending following materials together.
• Tablets were prepared by the procedure similar to that as described in said Pharmaceutical Agent Preparation Example 1, except that the product of Example 1 was employed as the active ingredient in the place of the product of Example 2.
• Each tablet contained 50 mg of the product of Example 1, as the active ingredient.
• Tablets were prepared by the procedure simlar to that as described in said Pharmaceutical Agent Preparation Example 1, except that the product of Example 3 was employed as the active ingredient in the place of the product of Example 2.
• Each tablet contained 50 mg of the product of Example 3, as the active ingredient.
• Tablets were prepared by the procedure similar to that as described in said Pharmaceutical Agent Preparation Example 1, except that the product of Example 5 was employed as the active ingredient in the place of the product of Example 2.
• Each tablet contained 50 mg of the product of Example 5, as the active ingredient.
• Tablets were prepared by the procedure similar to that as described in said Pharmaceutical Agent Preparation Example 1, except that the product of Example 8 was employed as the active ingredient in the place of the product of Example 2.
• Each tablet contained 50 mg of the product of Example 8, as the active ingredient.
• Some spiro-3-heteroazolidine compounds according to the invention were tested to evaluate their ability on reduction or inhibition of polyol increase in sciatic nerve of galactosemic rats.
• 30% galactose diet was fed and said compounds were orally administered at a dose of 10 mg/kg once a day for a period of 8 days.
• Control animals were received the galactose diet and were administered no such compound.
• One day after final administration on 9th day from the first administration), sciatic nerves were removed for galactitol determination.
• Results are shown in following Table 2 in terms of percent inhibition as compared to galactitol increase of the control animals.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Diabetes (AREA)
• Public Health (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• General Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Endocrinology (AREA)
• Obesity (AREA)
• Emergency Medicine (AREA)
• Hematology (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

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• 1985
  • 1985-03-04 JP JP60041234A patent/JPS61200991A/ja active Granted
• 1986
  • 1986-03-03 US US06/835,823 patent/US4740517A/en not_active Expired - Lifetime
  • 1986-03-04 EP EP86301530A patent/EP0193415B1/en not_active Expired - Lifetime
  • 1986-03-04 DE DE8686301530T patent/DE3679920D1/de not_active Expired - Lifetime

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